For many, the idea of intestinal fat absorption is not a pleasant thought. However, if you’re a biomedical researcher studying gut cells and lymphatic tissue, the need for proper lipid absorption is something that motivates your curiosity. Well now, a team of scientists at the Center for Vascular Research, within the Institute for Basic Science (IBS; South Korea) have just identified new subsets of gut connective cells, which are crucial for lymphatic growth. When food molecules reach your small intestine, specialized lymph capillaries, called lacteals, absorb fat nutrients. Lacteals are different from other lymphatics, as they continue to regenerate during adulthood, with a slow, but steady pace. The Korean scientists wanted to know more about how these cells grow and regenerate.

The walls of the small intestine are covered with fingerlike projections, called villi. Lining these villi, heterogeneous populations of epithelial, immune, vascular, connective, and even neural cells co-exist and help the digestive process. Lacteals and blood capillaries run inside the villi and take in different food molecules. The gut environment needs to cope with water secretion and reabsorption (osmotic stress), as well as the repetitive muscular activity that moves food through the intestine. How all these complex mechanisms are harmonized is still a mystery.

The research team was able to place a new piece towards completing this mysterious puzzle. Findings from their new study—published recently in Nature Communications through an article titled, “Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi”—showed that the regulatory proteins YAP/TAZ in villi’s connective cells, the intestinal stromal cells, play a role in the growth of nearby lacteals. In mice with an abnormal hyperactivation of YAP/TAZ, the team observed atypical sprouting of lacteals and impaired dietary fat uptake.

“The lacteals in these mice looked like tridents, which is very intriguing since we did not manipulate the lacteals themselves, but the surrounding cells,” noted co-lead study investigator Seon Pyo Hong, PhD, a research scientist at IBS.

The researchers took a step further and discovered that intestinal stromal cells belong to several subtypes, with distinct gene expression and localization within the villi. Among these subsets, three newly identified populations secrete VEGF-C—an essential molecule for lymphatic growth—upon YAP/TAZ activation.

“Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRβ+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake,” the authors wrote. “Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment.”

Co-lead study investigator Myung Jin Yang, PhD, a research scientist at the Korean Advanced Institute of Science and Technology, added: “We were very surprised to see such heterogeneity in a cell population that was considered homogeneous.”

In the last part of the study, the researchers showed that mechanical force and osmotic stress regulate YAP/TAZ activity in stromal cells. In summary, mechanical stimulation activates YAP/TAZ in the intestinal stromal cells, which in turn release VEGF-C and can account for lacteal growth.

Study co-author Hyunsoo Cho, PhD, noted: “This result implies a crucial link between the physiology of intestinal environment and biological interactions between cell types.”

“We are interested in investigating how each newly identified cell type works in healthy and diseased conditions,” concluded Gou Young Koh, PhD, professor, and director of the Center for Vascular Research at IBS.

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